Testosterone deficiency – defined as low levels of total testosterone in the presence of symptoms - is common among men with obesity and type 2 diabetes, with a reported prevalence of 58% and 45%, respectively.1,2 However, even after adjusting for age and BMI, the prevalence of subnormal free testosterone levels (<5 ng/dL or 144 pmol/L) in men with type 2 diabetes is higher than in men without (45% versus 33%).3

Here we summarize the results of a well conducted randomized, parallel, placebo controlled, double-blind, prospective trial that specifically selected men with type 2 diabetes based on low free testosterone levels (calculated free testosterone of <6.5 ng/dL on two occasions).4

In this study PSA levels did not change, and no subject developed hemoglobin >18 g/dL, hematocrit >55%, supranormal PSA concentrations (>4 ng/mL), or a prostate nodule during the trial.

What is known

Measuring SHBG and calculating free or bioavailable testosterone is advisable in men with type 2 diabetes, in whom low levels of free testosterone are consistently more common than low total testosterone levels.2,5-7

Several lines of research show that inflammatory mediators contribute to insulin resistance by interfering with insulin signaling.9,14-19 Long-term testosterone therapy has been shown to reduce CRP levels.20-22 However, the effect of testosterone therapy in men with type 2 diabetes on insulin resistance, measured by HOMA-IR, is unclear23, with studies showing either improvement in insulin resistance24 or no effect on insulin resistance.25

HOMA-IR is a commonly used index of insulin resistance.26,27 However, when investigating the effect of testosterone therapy on insulin resistance in men with type 2 diabetes, it has to be underscored that HOMA-IR is inaccurate because inadequate insulin secretion and beta-cell loss can lead to inappropriately low insulin concentrations and a falsely low HOMA-IR.27-29 The most accurate way to assess insulin resistance is through hyperinsulinemic-euglycemic (HE) clamps.

What this study adds

The study by Dhindsa used the HE clamp to investigate the effect of testosterone deficiency and treatment in type 2 diabetic men. In addition, detailed analysis of the expression of insulin signaling genes (IR-b, IRS-1, AKT-2, and GLUT4) in adipose tissue was conducted, as well as measurement of inflammatory mediators (CRP, interleukin-1b, tumor necrosis factor-a).

The men randomized to testosterone or placebo arms were similar in age (55 years), duration of diabetes (10 years), or use of anti-diabetes medications (primarily metformin, sulfonylureas and insulin). There was no significant difference in any of the baseline measures of body composition, insulin sensitivity, or inflammation of men randomized to testosterone or placebo arms.

1) Comparison of Eugonadal and Hypogonadal Type 2 Diabetic Men.

As expected, when compared to eugonadal men, hypogonadal men had larger waist circumference and more total body subcutaneous fat mass, as well as trunk fat and visceral fat mass, and less lean mass expressed as a percentage of total body weight. They scored lower on measures of sexual function and were more insulin resistant. The greater insulin resistance in hypogonadal men was primarily explained by visceral fat, hepatic fat, and total body subcutaneous fat.

Hypogonadal men also had lower expression of genes that mediate insulin signaling. However, there were no differences in expression of proinflammatory mediators known to interfere with insulin signaling (JNK-1, IKKb, SOCS-3, PTP-1B, and TLR-4 in MNC and in adipose tissue), nor inflammatory mediators (CRP, IL-1β, and TNF-α).

2) Results of Testosterone Treatment

Effects of 24 weeks of testosterone treatment on hormonal parameters and glucose are summarized in table 1. All listed changes in the testosterone group were statistically significant.

Despite reductions in fasting glucose and insulin, there was no change in HbA1c. There was also no change in serum lipids.

The testosterone group had an increase in lean body mass of almost 3 kg, and a reduction in total body subcutaneous fat of 2.4 kg. No body composition changes were seen in the placebo group. As illustrated in figure 1 and 2, Insulin sensitivity was significantly improved in the testosterone group, as indicated by a 32% increase in glucose infusion rate during the HE clamp, and insulin resistance (as indicated by HOMA-IR) was reduced accordingly.

Compared to placebo treatment, the expression of insulin signaling genes (Rb, IRS-1, AkT-2 and GLUT4) was significantly upregulated in adipose tissue after testosterone treatment. This was accompanied by a significant fall in circulating levels of FFA, CRP, IL-1β, TNF-α, and leptin, while there was no significant change in adiponectin levels. The reductions in CRP and were TNF-α were 19% and 16%, respectively. In mononuclear cells, testosterone treatment suppressed expression of proinflammatory and insulin resistance mediators (SOCS-3, IKK-b, and PTEN) as well as protein levels of SOCS-3. Notably, these changes in inflammatory mediators were not apparent until 15 weeks after the start of the treatment.

As expected, men in the testosterone group reported an improvement in some measures of sexual function. PSA levels did not change during the study. Hemoglobin and hematocrit increased by mean between-group difference of 0.54 g/dL and 2.3%, respectively (P = 0.10 and 0.03). No subject developed hemoglobin >18 g/dL, hematocrit >55%, supranormal PSA concentrations (>4 ng/mL), or a prostate nodule during the trial.

It was concluded that testosterone treatment in hypogonadal men with type 2 diabetes has insulin-sensitizing and anti-inflammatory effects in addition to a reduction in adiposity and an increase in lean body mass. The increase in expression of genes related to insulin signal transduction and the suppression of genes interfering with the action of insulin probably account for this insulin sensitizing effect. There is also an improvement in sexual function.

Comment

This study is notable in that it first compared hypogonadal and eugonadal type 2 diabetic men, and then treated those same hypogonadal men with testosterone to show improvements in hormonal, metabolic and inflammatory parameters. This study is also the first to demonstrate an insulin-sensitizing effect of testosterone therapy, using the gold standard HE clamp in hypogonadal men with type 2 diabetes.

While there were significant reductions in insulin resistance and fasting glucose, there was no change in HbA1c. This is likely because the duration of the study was too short to induce a change in HbA1c. Nevertheless, the evidence that testosterone increases insulin sensitivity and reduces fasting glucose concentrations is promising and suggests that long-term testosterone treatment may improve overall diabetes control. Support for this comes from multiple observational studies of long-term (5 to 10 years) testosterone treatment in men with obesity, metabolic syndrome and/or diabetes.20,21,30-33

It should be underscored that the improvement in inflammatory mediators did not emerge until 15 weeks (almost 4 months) after the start of testosterone therapy, and this study also suggests that even 6 months may be too short to show improvement in HBA1c. This is important to consider when offering patient with symptoms but low-normal testosterone levels – which is a common presentation in the clinic - a therapeutic trial to assess response to testosterone therapy. The Canadian34 and the US Endocrine Society35 guidelines recommend a therapeutic trial of only 3 months, while the International Society for Sexual Medicine guideline36 recommends 6 months. However, a previous randomized controlled trial of testosterone undecanoate in men with type 2 diabetes showed that improvements in insulin resistance and metabolic parameters continued for 12 months.37 This suggests that a therapeutic trial of a longer duration than 3-6 months may be warranted in men with metabolic dysfunction.

Overall, this well conducted RCT coupled with multiple observational studies of long-term testosterone treatment in real life clinical practices, provides evidence that testosterone therapy may help improve glycemic control in hypogonadal type 2 diabetic men, by conferring insulin-sensitizing and anti-inflammatory effects and improvement in body composition. This could possibly reduce need for anti-diabetic medications in hypogonadal diabetics receiving testosterone therapy.